Summary Basis of Decision for Loqtorzi

Clinical Pharmacology

Clinical pharmacology data support the use of Loqtorzi (toripalimab) for the specified indications.

Population pharmacokinetic studies showed that the pharmacokinetics of toripalimab was well described by a two-compartment model with zero-order intravenous infusion and time-varying clearance.

Coadministration of toripalimab and chemotherapy did not affect the pharmacokinetic profile of toripalimab. Weight-based dosing of toripalimab (3 mg/kg every 2 weeks) resulted in similar drug exposure as the fixed dosing regimen (240 mg every 3 weeks).

Body weight, albumin, lactate dehydrogenase, creatinine clearance, sex, and anti-drug antibody (ADA) status were not found to have any clinically meaningful impact on toripalimab exposure. Higher toripalimab exposure was observed in White and other non-Asian patients compared with Asian patients. However, these racial differences did not result in differences in efficacy or safety of toripalimab.

The population pharmacokinetic analysis indicated that patients who developed ADAs or neutralizing antibodies to toripalimab had slightly lower toripalimab exposure compared with those who tested negative. The impact of ADAs or neutralizing antibodies on the efficacy and safety of Loqtorzi is unknown due to the low incidence of these antibodies. In JUPITER-02 study, treatment-emergent ADAs were detected in 3.4% of the 146 evaluable patients with nasopharyngeal carcinoma who received Loqtorzi 240 mg every 3 weeks, in combination with gemcitabine and cisplatin, for a median duration of 15.1 months. Among the 190 evaluable patients with nasopharyngeal carcinoma in Cohort 3 of POLARIS-02 study who received Loqtorzi 3 mg/kg every 2 weeks for a median duration of 3.3 months, 3.7% of patients developed treatment-emergent ADA and 1.6% developed neutralizing antibodies.

Mild renal or hepatic impairment did not significantly impact the efficacy and safety of Loqtorzi. Only a small number of patients with moderate or severe renal or hepatic impairment were included in the studies; therefore, conclusions cannot be made on whether there are differences in the pharmacokinetics, safety, and efficacy of Loqtorzi in these patients.

For further details, refer to the Product Monograph for Loqtorzi, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The evidence of efficacy of Loqtorzi in combination with cisplatin and gemcitabine for the first-line treatment of adults with metastatic or recurrent, locally advanced nasopharyngeal carcinoma was provided from JUPITER-02, a randomized, multicentre, double-blind, placebo-controlled, Phase III study.

In addition, the evidence of efficacy of Loqtorzi as a single agent for the treatment of adults with recurrent unresectable or metastatic nasopharyngeal carcinoma with disease progression on or after a platinum-containing chemotherapy was derived from Cohort 3 of POLARIS-02, an open-label, single-arm, multicentre, multicohort, Phase II study.

JUPITER-02

JUPITER-02 included 289 patients with metastatic or recurrent, locally advanced nasopharyngeal carcinoma who had not received systemic therapy for metastatic or recurrent disease. The median age of patients was 48 years (range: 19 to 72 years), 4.8% of patients were 65 years of age or older, and 83% of patients were male. All patients were Asian, as the study enrolled patients from regions where nasopharyngeal carcinoma is endemic: China, Taiwan, and Singapore. The sponsor provided an acceptable discussion supporting the applicability of the JUPITER-02 results to a North American patient population. Furthermore, the results of a population pharmacokinetic analysis (see Clinical Pharmacology section) indicated that race is not expected to impact the efficacy or safety of Loqtorzi.

Patients had an Eastern Cooperative Oncology Group performance status score of 0 (57%) or 1 (43%). Eighty-six percent of patients had metastatic disease at study entry. The majority of patients (98%) had the non-keratinizing subtype of nasopharyngeal carcinoma, 1% of patients had keratinizing squamous cell carcinoma, and 1% of patients did not have the subtype identified.

Patients were randomized (1:1) to receive one of two regimens: 1) Loqtorzi 240 mg intravenously every 3 weeks in combination with cisplatin 80 mg/m² on Day 1 and gemcitabine 1,000 mg/m² on Day 1 and Day 8 of each 21-day cycle for up to 6 cycles, followed by Loqtorzi 240 mg every 3 weeks (146 patients), or 2) placebo in combination with cisplatin and gemcitabine for up to 6 cycles, followed by placebo once every 3 weeks (143 patients). Treatment continued until disease progression or unacceptable toxicity, or for a maximum duration of 24 months. The primary efficacy outcome measure was progression-free survival as assessed by a Blinded Independent Review Committee (BIRC) according to the Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1). Additional efficacy outcome measures included BIRC-assessed objective response rate and overall survival.

The prespecified interim analysis demonstrated that treatment with Loqtorzi in combination with cisplatin and gemcitabine resulted in a clinically meaningful and statistically significant improvement in the BIRC-assessed progression-free survival compared to placebo in combination with cisplatin and gemcitabine (hazard ratio [HR] = 0.52; 95% confidence interval [CI]: 0.359, 0.740; p = 0.003). Median progression-free survival was 11.7 (95% CI: 11.04, not estimable) months in the Loqtorzi arm and 8.0 (95% CI: 6.97, 9.53) months in the placebo arm.

The final analysis of the secondary endpoint of overall survival showed a statistically significant improvement in survival for the Loqtorzi arm compared to the placebo arm (HR = 0.63; 95% CI: 0.45, 0.89; p = 0.0083). The median overall survival was not reached in the Loqtorzi arm, while it was 33.7 months in the placebo arm. A higher percentage of patients in the Loqtorzi arm (77.4%) achieved an objective response compared to the placebo arm (66.4%). In the Loqtorzi arm, 19.2% of patients achieved complete responses versus 11.2% in the placebo arm. Partial responses were achieved in 58.2% and 55.2% of patients in the Loqtorzi arm and the placebo arm, respectively. A longer median duration of response was observed in the Loqtorzi arm (10 months) than in the placebo arm (5.7 months).

Cohort 3/POLARIS-02

Cohort 3 of POLARIS-02 evaluated Loqtorzi monotherapy in patients with recurrent or metastatic nasopharyngeal carcinoma that had progressed on or following platinum-based chemotherapy. The study was conducted at multiple medical centers in China.

Cohort 3 enrolled 190 patients who had received prior systemic therapy, with a median of two prior regimens (range: 1 to 13). Of these, 172 patients had received at least one prior platinum-based chemotherapy regimen and comprised the efficacy analysis set. The median age of patients was 45 years (range: 22 to 68 years), 4.1% of patients were 65 years of age or older, and 83% of patients were male. All patients were Asian. Patients had an Eastern Cooperative Oncology Group performance status score of 0 (37%) or 1 (63%). Ninety-nine percent of patients had metastatic disease, 95% had non-keratinizing nasopharyngeal carcinoma, 2.9% had keratinizing squamous cell carcinoma, and 1.7% did not have the subtype identified.

Patients received Loqtorzi 3 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity. The major efficacy outcome measures were confirmed objective response rate and duration of response as assessed by a BIRC using RECIST, version 1.1.

Treatment with Loqtorzi resulted in an objective response rate of 20.9% (95% CI: 15.1%, 27.8%) as assessed by the BIRC. Complete responses were achieved by 2.3% of patients, whereas 18.6% of patients achieved partial responses. The median duration of response was 14.9 months, indicating durable antitumour activity in this heavily pretreated population. Responses were observed across evaluated patient subgroups, including those with programmed death ligand-1 (PD-L1)-negative tumours and varying baseline levels of Epstein-Barr virus deoxyribonucleic acid. No clear relationship was observed between the aforementioned biomarkers and the treatment response. Although the single-arm design limits any comparative interpretations, the observed magnitude and durability of response are considered clinically meaningful given the lack of effective therapies in the setting of a nasopharyngeal carcinoma that has progressed on or after platinum-based chemotherapy.

Indication

The New Drug Submission for Loqtorzi was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Loqtorzi (toripalimab for injection) is indicated:

• in combination with cisplatin and gemcitabine, for the first-line treatment of adults with metastatic or with recurrent, locally advanced nasopharyngeal carcinoma.

• as a single agent, for the treatment of adults with recurrent unresectable or metastatic nasopharyngeal carcinoma with disease progression on or after a platinum-containing chemotherapy.

For more information, refer to the Product Monograph for Loqtorzi, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Loqtorzi 240 mg given intravenously every 3 weeks in combination with cisplatin and gemcitabine was evaluated in 146 patients in the clinical study JUPITER-02 (described in the Clinical Efficacy section).

The safety profile of Loqtorzi 3 mg/kg given intravenously every 2 weeks as a single agent was characterized based on data from 190 patients in Cohort 3 of POLARIS-02 (described in the Clinical Efficacy section) and from a pooled population of 851 patients across 12 clinical studies.

Loqtorzi in combination with cisplatin and gemcitabine

Among the 146 patients who received Loqtorzi in combination with cisplatin and gemcitabine in JUPITER-02, the median exposure to Loqtorzi was 15.1 months. Seventy-three percent of patients were exposed to Loqtorzi for 6 months or more and 54% of patients were exposed for one year or more.

The most commonly reported adverse reactions (occurring in at least 20% of patients) were nausea (71%), vomiting (68%), decreased appetite (55%), constipation (39%), hypothyroidism (38%), rash (36%), pyrexia (32%), diarrhea (31%), peripheral neuropathy (30%), cough (26%), musculoskeletal pain (25%), upper respiratory infection (23%), insomnia (23%), dizziness (21%), and malaise (21%).

Serious adverse reactions were reported in 43.2% of patients in the Loqtorzi arm and 43.4% of patients in the placebo arm. In the Loqtorzi arm, three (2.1%) fatal adverse reactions were reported: one due to epistaxis, one due to intracranial hemorrhage associated with immune-related thrombocytopenia and coagulopathy, and one due to pneumonia. Adverse reactions resulting in permanent discontinuation of Loqtorzi occurred in 12% of patients. Fifty percent of patients experienced adverse reactions leading to dosage interruptions.

Immune-mediated adverse reactions occurred with Loqtorzi, as expected for this class of product. The immune-mediated adverse reactions identified in the study are consistent with the known safety profile of the monoclonal antibodies that target either PD-1 or PD-L1. There is a potential for Loqtorzi to cause severe or life-threatening infusion-related reactions, as observed with other infused anti-PD-1 products.

Loqtorzi as a single agent

The safety profile of Loqtorzi as a single agent observed in POLARIS-02 was consistent with that observed in JUPITER-02 and with the established safety profile of the PD-1 inhibitor class. Among the 190 patients of Cohort 3, 33% were exposed to Loqtorzi for at least 6 months and 21% were exposed for more than one year. The most commonly reported treatment-related adverse events (occurring in at least 20% of patients) were hypothyroidism (27.4%), fatigue (22.1%), and cough (20%), the majority of which were Grade 1 or 2 in severity. Immune-mediated adverse events occurred in 24% of patients. Hypothyroidism was the most frequently reported immune-mediated adverse event. Fatal treatment-emergent adverse events, regardless of causality, occurred in 4.7% of patients. Treatment-emergent adverse events leading to permanent discontinuation of Loqtorzi were experienced by 9% of patients. Dosage interruptions due to an adverse reaction occurred in 23% of patients.

Key safety information from a pooled population of 851 patients who received Loqtorzi monotherapy at a dose of 3 mg/kg every 2 weeks across 12 clinical trials has been included in the Product Monograph for Loqtorzi. Among the 851 patients, there were 193 with nasopharyngeal carcinoma and 658 patients with other types of tumours. The most commonly reported adverse reactions (occurring in at least 20% of patients) were fatigue (22%), hypothyroidism (20%), and musculoskeletal pain (20%). The safety profile of Loqtorzi observed in this pooled population is consistent with that of the PD-1 inhibitor class. There were no new or unexpected safety signals identified.

The main safety concerns associated with the use of Loqtorzi are immune-related adverse reactions and infusion-related reactions. A Serious Warnings and Precautions box was included in the Product Monograph for Loqtorzi to highlight that Loqtorzi can cause severe and fatal immune-mediated adverse reactions, which can occur in any organ system or tissue; severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis; and that fatal and other serious complications can occur in patients who undergo allogeneic hematopoietic stem cell transplantation before or after being treated with a PD-1/PD-L1 blocking antibody. Recommended treatment modifications to manage immune-mediated adverse reactions and infusion-related reactions are listed in the Product Monograph for Loqtorzi.

For more information, refer to the Product Monograph for Loqtorzi, approved by Health Canada and available through the Drug Product Database.

Toripalimab, the medicinal ingredient in Loqtorzi, is a humanized immunoglobulin G4 (IgG4) kappa monoclonal antibody directed against the programmed death 1 (PD-1) receptor. Binding of toripalimab to PD-1 blocks the interaction of PD-1 with its ligands, programmed death ligand-1 (PD-L1) and PD-L2, thereby releasing PD-1 pathway-mediated inhibition of the immune response, including the antitumour immune response.

The submitted non-clinical studies of toripalimab characterized its binding affinity, species cross-reactivity, and binding kinetics in vitro. No off-target binding or specific tissue cross-reactivity with toripalimab was noted in cynomolgus monkey or human tissues. The antibody does not bind to mouse or rat PD-1.

Toripalimab has the potential to enhance T-cell recall responses to antigens, as shown with other authorized monoclonal antibodies that target PD-1 or PD-L1. It did not induce antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity. The desired pharmacological effect was demonstrated in vivo with syngeneic and xenograft mouse models of cancer in which toripalimab slowed the tumour growth.

Repeat-dose toxicity studies of toripalimab in cynomolgus monkeys did not identify significant adverse effects at doses up to 100 mg/kg administered by intravenous infusion once weekly for 26 weeks or biweekly for 4 weeks. Based on these results, the dose of 100 mg/kg is considered the no-observed-adverse-effect level (NOAEL) in cynomolgus monkeys.

The repeat-dose toxicity studies also evaluated safety pharmacology parameters and showed that there were no adverse effects on the cardiovascular, respiratory, or central nervous systems.

No adverse effects were observed in the reproductive organs of male and female cynomolgus monkeys in the 4- or 26-week repeat-dose toxicity studies. Reproductive and development toxicity studies with toripalimab were not considered necessary given the established role of the PD-1/PD-L1 pathway in maternal immune tolerance to fetal tissue. Previous animal studies have demonstrated that inhibition of the PD-1/PD-L1 pathway can lead to an increased risk of immune-mediated rejection of the developing fetus resulting in fetal death. Immunoglobulin G4 is also known to cross the placental barrier; hence, toripalimab has the potential to cross the placenta during pregnancy and cause harm to the fetus. Accordingly, the Product Monograph for Loqtorzi specifies that the use of Loqtorzi is not recommended during pregnancy and in women of childbearing potential not using effective contraception.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Loqtorzi. In view of the intended use of Loqtorzi, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Product Monograph for Loqtorzi, approved by Health Canada and available through the Drug Product Database.

Characterization of the Drug Substance

Toripalimab is a recombinant humanized immunoglobulin G4 (IgG4) kappa monoclonal antibody. It binds to the programmed death 1 (PD-1) receptor and blocks its interaction with programmed death ligand-1 (PD-L1) and PD-L2, thereby releasing the PD-1 pathway-mediated inhibition of the immune response, including the antitumour immune response.

The antibody is composed of two identical heavy chains and two identical light chains joined by disulfide bonds. Each light chain contains 219 amino acids, and each heavy chain has 452 amino acids. The approximate molecular weight of toripalimab is 147 kDa.

Detailed characterization studies were performed to provide assurance that toripalimab consistently exhibits the desired characteristic structure and biological activity.

Results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits. A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risk of the formation or introduction of nitrosamines during the manufacturing process is considered negligible or low; therefore, no confirmatory testing is required.

Manufacturing Process of the Drug Substance and Drug Product and Process Controls

Toripalimab is manufactured using a Chinese hamster ovary cell line genetically engineered to express the protein. The cell culture process is initiated with the thawing of one vial of the working cell bank. Cells are expanded through a series of steps and then transferred into a production bioreactor that uses a fed-batch process. The bulk harvest is prepared by depth filtration prior to downstream processing. The purification process for the secreted protein is typical for monoclonal antibodies and consists of chromatography, virus inactivation, and filtration steps. Subsequently, the bulk drug substance is formulated, filtered, filled into bags, and stored at or below -40 °C.

The drug product manufacturing process includes drug substance thawing, mixing, bioburden-reduction filtration, sterile filtration, and aseptic filling into glass vials. The filled vials are stoppered, capped, visually inspected, labelled, and packaged. The final drug product is stored at 2 °C to 8 °C. None of the non-medicinal ingredients (excipients) in Loqtorzi are prohibited for use in drug products by the Food and Drug Regulations. The compatibility of toripalimab with the excipients is supported by the stability data provided

The sponsor has adequately identified critical and key process parameters and in-process controls based on process development, process characterization, and previous manufacturing experience. The process validation data demonstrate that the manufacturing process consistently produces toripalimab and Loqtorzi of acceptable quality.

Control of the Drug Substance and Drug Product

The release and stability specifications for the drug substance and drug product are appropriately set and justified. Analytical procedures used in the release and stability testing of the drug substance and drug product have been adequately validated. In addition, the primary and working reference standards have been adequately qualified. The protocol for the qualification of new working reference standards is acceptable.

Loqtorzi is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per the Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory.

The shelf life of 36 months for the drug product, when stored at 2 °C to 8 °C, is considered acceptable.

The compatibility of the drug product with the container closure system was demonstrated through stability studies and studies of extractables and leachables.

Facilities and Equipment

Based on the information submitted, an on-site evaluation of the drug substance and drug product manufacturing site was not deemed necessary.

The design, operations, and controls of the facilities and equipment involved in the production are considered suitable for the activities and products manufactured. The manufacturing site is compliant with good manufacturing practices.

Adventitious Agents Safety Evaluation

The manufacturing process of the drug substance incorporates adequate control measures to prevent contamination and maintain microbial control.

Master cell banks, working cell banks, and end-of-production cell banks undergo thorough testing for detectable adventitious agents (bacteria, fungi, mycoplasma, and viruses). The cell culture process includes in-process tests to monitor for bioburden, endotoxins, mycoplasma, and viruses. Scaled-down viral clearance studies demonstrate that the downstream purification process is capable of inactivating or removing model viruses with diverse physicochemical characteristics.

No raw materials of human or animal origin were used during cell bank preparation, drug substance and drug product manufacturing. Materials of animal origin used during cell line development were properly sourced and tested. Accordingly, the risk of contamination of the drug product with bovine spongiform encephalopathy and transmissible spongiform encephalopathy agents is considered negligible.

The excipients used in the drug product formulation are not of animal or human origin.